Substituted barbituric acids con



Patented June 6, 1939 UNITED STATES SUBSTITUTED BARBITURIG V ACIDS CON-TAINING QUATEENARY CARBON ATOMS Frank O. Whitmore, State College, Pa.,and Melvin A. Thorpe, St. Louis, Mo., assignors to Mallinckrodt ChemicalWorks, St. Louis, Mo;

No. Drawing.

ApplicationNovember 3, 1934, Serial No. 751,416 L Y Claims. (or. 260-257) This invention relates to substituted barbituric acids, and withregard to certain'rnore specific" wherein Y indicates hydrogen or alkalimetal; and the Rs indicate alkyl or othersubstituent groups (as pointedout'more fully hereinafter),

but at least one of the Rs indicates an alkyl substituent containing aquaternary carbon'atom, that is, a carbon atom to which are linked fourother carbon atoms; or the ordinary substitution products thereof. Otherobjects will be in part obvious and in part pointed out hereinafter. Theinvention accordingly comprises the elements and combinations ofelements, and features of composition, which will be exemplified in thesubstances hereinafter described, and the scope of the application ofwhich will be indicated in the following claims.

It has heretofore been determined that the effectiveness of substitutedbarbituric acid derivatives as hypnotics, jsedatives, or soporifics,depends in part upon the composition of the substituent groups, and ithas also been noted that the more branched the substituent groups are,the more effective is the hypnotic or sedative or soporific action,without correspondingincrease in undesirable qualities. It is thepurpose of the present invention to provide for substituted barbituricacids having substituents including a considerable number .of branchesthrough the use of substituents containing a quaternary carbon atom,which substituents are all broadly new. Such derivatives have notheretofore been prepared because no satisfactory method has been knownfor obtaining the quaternary carbon-containing substituent in such formas to permit of its joining to: the barbituric acid nucleus. However,such a method has now been provided, and, as set forth in the'copendi-ngapplication of the present applicant Whitmore, and Walter E. Trent,Serial No. 666,510, filed April 17, 1933, now Patent No. 2,022,485,dated November 26, 1935, halides including a quaternary carbon atom,such as 3,3-dimethyl-l-bromobutane, may readily be prepared. In thecopending application of the present applicant Whitmore and August H.I-Iomeyer, Serial No. 36,132 filed An gust 14, 1935, the preparation ofhigher homologous halides, such as 4,4-dimethyl-1-bromopentane,isdisclosed.

Numerous examples of substances within the scope of the invention areset forth hereinafter, and for an exemplary number of these examples,details of procedure for the preparation thereof are set forth. It is tobe understood, however, that the invention is by no means limited to thespecific examples set forth.

The first group of examples, numbered 1 through 5, show variations inthe structure of the substituent R' (in the above type formula)containing the quaternary carbon atom, while the other R. is uniformlythe substituent ethyl.

. EXAMPLE 1 5 -ethyl, 5- (3,3'-dimethylbutyl) barbituric acid Thestructural formula of this substance is as follows: 7

CHa-CH2 OZ-CNH The above substance is prepared in the following manner:

Ethyl ethylmalonate, commercially obtainable, is used as a startingmaterial. This substance is condensed, in absolute ethyl alcohol in thepresence'of an alkali alcoholate, with 3,3- dir'nethyl-l-bromobutane,according to the following reaction:

The product of this reaction, the formula for which is given above, isthen condensed with urea, the reaction proceeding in the followingmanner:

onion; o=c-:o'r'r;6ii;"fi[-Nn the product being the desired substitutedbarbituric acid.

Procedure 150 cc. of ethyl alcohol were distilled from a solution ofabsolute ethyl alcohol plus onetwentieth of its weight of metallicsodium into a three-neck flask. The flask was placed in an oil bath anda condenser holding a drying tube at the upper end, and a stirrer with amercury seal, and a dropping funnel were placed in the three necks. 6.9grams of metallic sodium weighed in toluene were added in small piecesthrough the condenser over a period of about 7 minutes. Then, with theoil bath at a temperature of about C., 56.4 grams of ethyl ethylmalonate(boiling point, 112 to 115 at 30 to 32 mm. pressure) were added and themixture was stirred for about one-half hour. Then, during the next twohours, 49.5 grams of 3,3-dimethyll-bromobutane (boiling point, 137 to138 C. at 746 mm. pressure), were added to the mixture. After aboutone-half hour, sodium bromide began to settle out. The mixture was thenstirred and refluxed for 56 hours, at the end of which time the mixturewas just faintly alkaline to litmus paper. The flask was then attachedto a fractionating column and the excess alcohol distilled oii. Theresidual mixture was washed with cc. of water and the oily layer allowedto separate. The water layer was extracted once with ether, and theether was then added to the oily fraction, which was then dried withsodium carbonate. The dried oily fraction was then fractionated, and theproduct ester (see structural formula above), was obtained to the extentof 36.1 grams, boiling at from 148 to 151 C. The yield was 44% oftheoretical. The index of refraction of the product ester was about1.4320 at 20 C., with respect to the sodium-D line.

The same flask arrangement was used for the second step. 65.97 grams ofabsolute ethyl alcohol were placed in the flask, and 3.84 grams of cleanmetallic sodium were added to form sodium ethylate. The resultingethylate was cooled to 20 C., and 15.15 grams of the ester prepared asabove were added, followed by 4.81 grams of pure, crystalline urea. Thereaction mixture was heated to refluxing temperature by means of a waterbath, and the refluxing was continued for four hours. A straightcondenser was then attached to the flask, and the excess alcohol wasremoved by distillation. This required two hours. The residue in theflask was then cooled to 25 C., and then dissolved by adding 50 cc. ofdistilled water. The resulting solution was then extracted with twoportions of ether, 50 cc. and 25 cc. respectively. The extractedsolution was then diluted with an additional 50 cc. portion of water andthe barbituric acid derivative precipitated out by adding dilutehydrochloric acid until the solution was. acid to blue litmus paper. Thealmost white crystalline precipitate was washed with water, sucked freeof excess water, and then dried in an electric drying oven over night at105 C. The product weighed 9.35 grams, which was 70% of the theoreticalyield. This product was then dissolved in 107 cc. of boiling 50% ethylalcohol. On cooling, 8.5 grams of pure white crystals were obtained.These crystals had a melting point of about 192 C., and constituted thedesired product, 5-ethyl, 5-(3',3'dimethy1 butyl) barbituric acid.

EXAMPLE 2 5 -ethyl, 5- (4',4-dimethylpentyl) barbitzm'c acid 'Thestructural formula of this substance is as follows:

omen? O:ONH

O C: (oflosocmomom o ;c1 u1 from which it is seen that it is the same asthe preceding compound, Example 1, except for the addition of onefurther -CH2- group in the alkylene chain connecting the quaternarycarbon atom to the barbituric acid nucleus.

The synthesis of this substance is substantially the same as that of thenext lower homologue (Example 1) as described, but involving the use of4,4-dimethyl-l-bromopentane in place of the 3,3-dimethyl-1-bromobutane.First, the 4,4-dimethyl-l-bromopentane is condensed with ethylethylmalonate to obtain the ester having the formula:

and that is in turn condensed with urea to obtain the desired product.Because of the similarity of procedures, no detailed example of thesynthesis of this material will be given.

The product, 5-ethyl, 5-(4',4-dimethylpentyl) barbituric acid, is acrystalline solid'having a melting point of about 184 to 185 C.

, EXAMPLE 3 5-e thyl, 5-(4,4'-dimethylhea:yl) barbiturz'c acid Thestructural formula of this substance is as. follows:

O:C-NH' 0 C20 I CHaCHa.C(CHa)2.CHz.OHz.CH2 0ZC'NH anionic(cnmcmomonf cooomorn and that is in turn condensed with urea to obtain the desiredproduct which has the form of long, colorless. fluffy needles melting at154 to 155 C.

EXAMPLE 4 5 ethyl, 5- (7',7"dimethyloctyl) barbituric' acid Thestructural formula of this substance is as follows:

CHLOE?! O:C-NH

o l (CH3)3C.CH2.CHa.OHz.CH2.CHz-CH2 OZC-NH from which it is seen that itis the same as the substances of Examples 1 and 2, except for theaddition of four, and three, respectively, further -CH2 groups in thealkylene chain connecting the quaternary carbon atom to the barbituricacid nucleus.

The synthesis of this substance is substantially the same as that of thepreceding examples, but involving the use of .7,7-dimethyl-1-bromooctaneas the quaternary carbon-containing starting material. This, is firstcondensed with ethyl ethylmalonate to obtain the ester having theformula:

- (CH1)3C.CH2.GH2.CH2.CHLCH2-CH2 OZC-OCHzCHs and that is in turncondensed with urea to obtain the desired product.

The foregoing examples illustrate the possibility of numerous variationsin the structure of the substituent group containing the quaternarycarbon atom. For illustrative purposes, the other substituent group has,throughout these examples, been held as ethyl. In the next thirteenexamples, numbered 5 through 17, inclusive, the substituent containingthe quaternary carbon atom remains the same, namely,4',4'-dimethylpentyl- (see Example 2), while the other substituent issubjected to wide variations.

EXAMPLE 5 5- (4',4dimethylpentyl) barbituric acid This substance has thefollowing structural formula:

H\ (yo-tin a 0 0:0

l (CH3)3C.CH2.CH2.CH2 OZC-NH It represents a substance where the secondsubstituent is hydrogen.

This substance is synthesized by first condensing ethyl malonate with4,4-dimethyl-l-bromopentane, in absolute ethyl alcohol in the presenceof an alkali alcoholate, according to the following reaction:

+NaBr The product of this reaction, the formula for which is givenabove, is then condensed with urea, the reaction proceeding in thefollowing manner:

the product being the desired substance, 5-(4',4'-

dimethylpentyl) barbituric acid.

Ethyl malonate, the starting material, is commercially obtainable.

v EXAMPLE 6 5-methyl, 5- (4,4-dimethylpentyl) barbituric acid Thissubstance has the following structural formula:

- OzC-NH It is representative of a class of substances where the secondsubstituent is an alkyl, specifically, methyl. Examples 1 through 4 alsofall in this category, the second substituent there being ethyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl methylmalonate in place of the ethyl malonate. Ethylmethylmalonate is commercially obtainable.

EXAMPLE '1 5-n-pr0pyl, 5 (4 ',4'-dimethylpentyl) barbituric acid Thissubstance has the following structural formula:

CHa.GH2.0Hz -NH o l (CH3 80.0Hfl.CHq-CH2 O:C-NH

It is likewise a substance in which the secondsubstituent is an alkyl,specifically, n-propyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl n-propylmalonate in place of the ethyl malonate. Ethyln-propylmalonate is commercially obtainable.

EXAMPLE 8 5 -n-batyl, 5- (4',4-dimethylpentyl) barbituric acid Thissubstance has the following structural formula GHLCHI-GHi-GHz (pC-NH(CHalaQOHaCHsCHa O:C--N

It is likewise a substance in which the second substituent is an alkyl,specifically, n-butyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl n-butylmalonate in place of the ethyl malonate. Ethyln-butylmalonate is commercially available.

EXAMPLE 9 5-allyl, 5- (4',4'-dimethylpentyl) balrlnturz'c acid EX MPLE10 5-propargyl, 5- (4,4 -dimethylpentyllbarbituric acid 5 -cyclopentyl,5 (43 4. -dime.thylpentyl) barbituric acid This substance has thefollowing structural formula:

CHYIJH OZC-JITH C C20 l (cHoaQcHscHscm OzC-NH This substance isrepresentative of a class of substances in which the second substituentis a cycloalkyl, specifically, cyclopentyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl cyclopentylmalonate in place of the ethyl malonate. Ethylcyclopentylmalonate may be prepared by wellknown methods.

E AMPLE l2 5 -cyclohexyl, 5- (4',4'-dimethylpentyl) barbituric acid Thissubstance has the following structural formula:

It is likewise representative, along with Example 11, of substances inwhich the second substituent is a cycloalkyl, specifically, cyclohexyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl cyclohexylmalonate in place of the ethyl malonate. Ethyl Vcyclohexylmalonate may be prepared by wellknown methods.

1 1 EXAMPLE l3 5-phenyl, 5- (4,'4'dimethylpentyl) barbitaric acid Thestructural formula of this substance is as follows:

C5115 OZCNH It is representative of a class of derivatives in which thesecond substituent is an' aryl, specificially, phenyl.

It is prepared by the same method of synthesis as that of Example 5,using ethyl phenylmalonate in place of the ethyl malonate. Ethylphenylmalonate is commercially obtainable. The product has the form ofwhite crystals which melt at 174 to 175 C.

EXAMPLE 14 s-b'enzyz, 4,'4-dimethylpentyl) barbituric acid Thestructural formula of this substance is as follows:

CaHt.CH2 A O:CNH

O cnmdcraomom sic-i111 It is representative of a class of derivatives inwhich the second substituent is an arylalkyl, specifically, benzyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl benzylmalonate in place of ethyl malonate. Ethylbenzylmalonate is commercially obtainable.

EXAMPLE 5- (beta-phenyletii'yl) 5- (4';4'-dimethylpentyl) barbiturz'cacid The structural formula of this'substance is as follows:

CtH5.CH2.CH2 -O:C-NH.

0 1 I (CHa)aC.CH2.CHz.CHz OzC-NH It is representative, along withExample 14, of derivatives in which the second substituent is anarylalkyl, specifically, beta-phenylethyl,

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl .betaphenylethylmalonate in place of the ethyl malonate.Ethyl beta-phenylethylmalonate is commercially obtainable.

7 EXA PLE 16 5 -phenoxyethyl, 5- (4 ,4 -dzmethylpentyl) barbituric acidThe structural formula of this substance'is as follows: 4

CaHLOlCHLQHz O:O-NH

. c r l (CH3)3C.CE2.CH2.CH2 OIC-NH 7 It is exemplary of a class ofderivatives in which the second substituent is an aryl-oxy-alkyl,specifically, phenoxyethyl.

It is prepared by the same method of synthesis as that of Example 5, butusing ethyl phenoxyethylmalonate in place of the ethyl malonate. Ethylphenoxyethylmalonate may be prepared by well-known methods.

EXAMPLE 1'7 5 -etho.ryethyl, 5- (4,4dimcthylpentyl) barbituric acid Thestructural formula of this substance is as follows:

(cmboomcmcm O:CNH

It is exemplary of a class of derivatives in which the secondsubstituent is an alkyl-oxy-alkyl, specifically, ethoxyethyl.

It is prepared by the same method of synthesis as that'of Example 5, butusing ethyl ethoxyethylmalonate in place' of the ethyl malonate. Ethylethoxyethylmalonate may be prepared by well-known methods.

A still further generic class of derivatives coming within the scope ofthe invention comprises the monobasic alkali metal salts of any of thecHicHtocHacHi acids falling within the scope of the invention. Forexample, if sodium ethylate be allowed to react, in molecularproportions, by well-known methods, with any of the foregoing acids, themonobasic sodium salt of the corresponding acid is obtained. The same isof course true of the other alkali metals. It is unnecessary herein toset forth specifically all of these alkali-metalsalts of all of theforegoing acids, but a few will suffice for the lot:

EXAMPLE 18 (From Example 1.) Monobasic sodium salt of -ethyl,5-(3',3'-dimethylbutyl) barbituric acid.

EXAMPLE 19 (From Example 2.) Monobasic sodium salt of 5-ethyl,5-(4,4'-dimethylpenty1)barbituric acid.

EXAMPLE 20 (From Example 13.) Monobasic sodium salt of 5-phenyl,5-(4,4-dimethylpentyl) barbituric acid, which is an amorphous Whitepowder that decomposes on heating, yielding no well-defined meltingpoint.

The malonic esters described in this application are claimed in thecopending application of the present applicant Whitmore, and David M.Jones and Clarence I. Noll, Serial No. 63,212, filed February 10, 1936.

In View of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results obtained.

As many changes could be made in carrying out the above syntheses and incompounding the above substances without departing from the scope of theinvention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limit- 7ing sense.

5- (3',3' -dimethylbutyl) barbituric 5- (4',4' -dimethylpentyl)barbituric wherein Y indicates a substituent selected from a classcomposed of hydrogen and the alkali metals, R indicates a substituentselected from a class composed of hydrocarbon radicals, aryloxy-alkyls,and alkyl-oxy-alkyls, R1 is an aliphatic hydrocarbon radical, and R2,R3, and R4 are each alkyls attached to the same carbon atom of R1.

4. A 5-substituted barbituric acid having a single barbituric acidnucleus, in which one of the substituents in the 5-position is analiphatic hydrocarbon radical having a quaternary carbon atom in itsstructure.

5. A 5-substituted barbituric acid having a single barbituric acidnucleus, in which one of the substituents in the 5-position is an alkylhaving a quaternary carbon atom in its structure.

FRANK C. WHITMORE. MELVIN A. THORPE.

